Research on the cell cycle seeks to understand the signals that inhibit or stimulate cell division and the mechanisms that transmit these signals to cellular targets. Cell division is intimately connected to growth and development and is therefore important for developmental diseases, birth defects, chromosome damage, aging and regeneration, as well as diseases of proliferation, such as cancer and atherosclerosis. Recently work supported by this grant and other work in many laboratories has identified the central components that regulate cell division. Cell division is regulated by the accumulation of unstable proteins called cyclins, which activate protein kinases in the cdc2 family, which serve as master regulators of the cell cycle. We plan to extend this work in three directions: 1) To study the regulation of the stability of the cyclin proteins and the mechanism of rapid cyclin degradation at specific points in the cell cycle. Biochemical experiments in frog egg extracts will examine the signals and steps in cyclin degradation. Genetic and biochemical experiments in yeast are aimed at identifying new molecules in the cyclin destruction pathway. 2) To study the steps in the cell cycle regulated by the G1 cyclins and to study the posttranslational regulation of these proteins. Both biochemical and genetic work in yeast will be combined with transfection experiments in mammalian cells to understand what events are regulated by G1 cyclins and what regulates the activity of the cdc2 kinase. The expression of G1 cyclins in frog embryos will be related to the different cyclin proteins. 3) To study the feedback inhibition by DNA damage through the weel pathway. Through biochemical experiments and genetic experiments in yeast we will study the pathway by which the cell responds to DNA damage and inhibits the cell cycle through the weel kinase.